In donor eyes with macroscopically normal fundi, the number of rod photoreceptors decline steadily from mid-life, particularly in the parafoveal, whereas the number of cones is stable. We propose to test 3 related hypotheses using two sources of human eyes: 1) Eye Bank donors eyes obtained within 2 hr of death, and 2) eyes obtained at surgery from cancer patients who have had pre-operative eye exams, testing of visual function, and fundus photography. Preserved eyes from both sources will be graded for macular changes. Hypothesis 1: Age-related cell loss in central retina includes the small population of blue-sensitive cones, thought on the basis of clinical and psychophysical evidence to be preferentially vulnerable to aging. Using immunocytochemistry and an antibody to the human blue opsin, we will determine if the number of labeled cones is reduced in retinas from donors over age 70 compared to donors aged 40-59 yr that we studied previously. Hypothesis 2: Outer segments of rods surviving age-related rod loss expand to maintain constant total rhodopsin. Decreased scotopic sensitivity is due to post- receptoral factors. Because fundus reflectrometry evidence suggests that rhodopsin content in central retina is stable with age despite decreasing rod number, we will measure rhodopsin content using spectrophotometry and rod density and outer segment volume using quantitative light microscopy in the central retina of fellow eyes in young (<50 yr) and old donors. The next neuron in one of the 2 major intra-retinal pathways transmitting rod information to ganglion cells in the rod bipolar cell. Using immunocytochemistry and an antibody to protein kinase C, we will determine the number of rod bipolar cells in young adult and aged donor eyes, and using electron microscopy, we will determine diverge and convergence between rods and rod bipolars. Hypothesis 3: The vulnerability of the parafoveal for age-related photoreceptor loss, as well as for geographic atrophy of the pigment epithelium (PE), and the sparing of foveal cones is related to regional differences in the underlying PE and Bruch's membrane (BM). In order to determine if PE cell loss accompanies rod loss, we will quantify the topography of PE cell spatial density and volume in retinas of different ages with known photoreceptor topography using quantitative light microscopy. Although rod loss occurs in retina without the grossly visible changes typical of macular degeneration, most of adult retinas contain drusen and basal laminar deposit (BLD), and the simplest explanation for rod loss is the presence of subclinical pathology of PE and BM. Therefore, we will compare the relatively spared fovea and the vulnerable parafoveal for the presence of BLD seen by electron microscopy. By using specimens in which the retina remains attached to the PE and by cutting tissue blocks in both vertical and tangential planes, PE and BM fine structure will be related to underlying photoreceptor cell number.